Tumor Necrosis Predicts Benefit From Hypoxia-modifying Therapy in High-Risk Bladder Cancer

The addition of carbogen and nicotinamide (hypoxia-modifying agents) to radiation therapy improves the survival of patients with high risk bladder carcinoma, however, there is no predictive biomarker of response to treatment in routine clinical use. We investigated the ability of tumor necrosis to predict benefit from hypoxia-modifying therapy in high grade bladder cancer. Tumor samples were obtained from a subset of 231 patients enrolled in the BCON phase III randomized controlled trial of radiation therapy alone or with carbogen and nicotinamide. Tumor necrosis (TN) was scored as present or absent from whole tissue histological sections stained with H&E. Carbonic anhydrase IX (CAIX) and glucose transporter 1 (Glut1), and proliferation (Ki67) were also explored using paraffin-embedded tissue obtained at diagnosis. Results were interpreted with respect to overall survival. TN was identified in 121 patients (52%). Five year overall survival was 41% for the RT arm and 48% for the CON arm (log rank p = 0.14). TN was a prognostic factor for patients treated with radiation therapy (p = 0.014). CAIX (p = 0.0001) and Glut1 (p = 0.013) showed significant association with tumor necrosis, but Ki‑67 did not. When stratified by TN, the 5-year overall survival estimates were 48% (RT) and 39% (CON) (log rank p = 0.32) in patients with no evident TN and 34% (RT) and 56% (CON) (log rank p = 0.004) in patients with TN. There was a significant treatment by necrosis strata interaction (p = 0.007) and this remained after multivariate analysis (p = 0.001). After adjustment for age, hemoglobin, TURBT, stage, gender and CIS in a stratified Cox regression model the presence of TN was a significant predictor of benefit from CON compared to RT alone (HR 0.43, 95% CI 0.25-0.73, p = 0.002). This benefit was not observed when there was no evident TN (HR 1.64, 95% CI 0.95-2.85, p = 0.08). Assessment of tumor necrosis has potential for selecting patients with high grade and muscle invasive bladder carcinoma suitable for hypoxia-modifying therapy. It is simple to identify and can easily be incorporated into routine histopathological examination.